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Genome analysis for MDS among A-bomb survivors
ATM protein is a key molecule in DNA damage response, in particular, for DSB caused by ionizing radia- tion,25,26,27 and it is possible that the loss of one allele of ATM was the initial event for clonal selection towards the development of MDS among A-bomb survivors. It is assumed that immature hematopoietic cells that lost ATM following A-bomb radiation either responded poorly or incorrectly to other DNA damage generated at the same time. This might also explain why TET2 mutations, which are common in de novo MDS, and are usually thought to be an initiating mutation for de novo MDS, were observed at a low frequency in the PE group in this study. Considering the gain-of-function alterations of KMT2A and CBL in MDS,28,29,30 the defect in ATM func- tion generated by 11q deletion that has also been found in de novo MDS3,22 would have a greater impact on the ini- tiation of MDS among A-bomb survivors. It is necessary to investigate whether alterations in ATM, rather than TET2, are frequently present in A-bomb survivors who have clonal hematopoiesis of indeterminate potential (CHIP).
In conclusion, we reported a profile of genetic alter- ations in MDS among survivors exposed to A-bomb radi- ation, such as fewer mutations in genes along DNA methylation pathways, and frequent 11q deletions and
aberrations in ATM. Further investigations are warranted to elucidate the role of these genetic alterations in the pathogenesis of MDS after radiation exposure.
Funding
This work was partly supported by JSPS KAKENHI (Grant Number 26461426) (Y. Miyazaki), MEXT KAKENHI (Grant number 17H04209) (K-IY, Y. Miyazaki), the Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science (MT, MH, K-IY, Y. Miyazaki), the Takeda Science Foundation (K-IY, Y. Miyazaki), Practical Research for Innovative Cancer Control (Grant number 16ck0106073h0003) (SO), the Project for Cancer Research and Therapeutic Evolution (Grant number P-CREATE, 16cm0106501h0001) from Japan AMED (SO), and JSPS KAKENHI (Grant number 15H05909) (SO).
Acknowledgments
We thank Mariko Yozaki, Naoko Ito, Hiroe Urakami, Azumi Yukawa, and Chihiro Yoshikawa for their technical assistance, and Natasha Beeton-Kempen (Edanz Group, www.edanzedit- ing.com/ac) for editing a draft of this manuscript.
For original sequence data, please contact Masataka Taguchi (mtaguchi-ngs@umin.org), and Yasushi Miyazaki (y- miyaza@nagasaki-u.ac.jp).
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